Exposure-response and dose simulation of belantamab mafodotin in combination with standards of care in patients with relapsed/refractory multiple myeloma.

Belantamab mafodotin is approved globally for relapsed/refractory multiple myeloma (RRMM) based on the phase 3 DREAMM-7 (belantamab mafodotin, bortezomib, dexamethasone [BVd]) and DREAMM-8 (belantamab mafodotin, pomalidomide, dexamethasone) studies. Ocular events in these studies were common, transient, and associated with high rates of resolution. Exposure-response analyses using Cycle 1 exposures (data from the DREAMM-6, DREAMM-7, and DREAMM-8 trials) and BVd dosing regimen simulation (using a previously-developed and validated framework) were performed to support benefit-risk analysis of belantamab mafodotin dosing strategies to improve outcomes. Higher Cycle 1 belantamab mafodotin exposure was significantly associated with higher probabilities of overall response, very good partial response or better (≥VGPR), and shorter time to response, as well as ocular events including grade ≥2/≥3 ophthalmic exam findings (OEFs), and best-corrected visual acuity worsening to 20/50 or worse in both eyes. However, multivariate models predicted that the benefit of increased probability of ≥VGPR with a 2.5 mg/kg vs 1.9 mg/kg starting dose (70.4% vs 54.3%) outweighed the risk for modest increases in clinically meaningful ocular events. Simulated regimens with a 2.5 mg/kg first dose demonstrated high efficacy, with regimens that stepped down to 1.9 mg/kg and utilized schedule extensions (planned or in response to ocular events) showing improved tolerability. Altogether, a belantamab mafodotin starting dose of 2.5 mg/kg in RRMM is important to achieve deeper response and outweighs modest improvements in tolerability from a 1.9 mg/kg starting dose. Subsequent step-down to 1.9 mg/kg along with schedule extensions can be used to manage tolerability while still achieving meaningful efficacy.